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Review
. 2012 Feb 10;18(1):47-55.
doi: 10.2119/molmed.2011.00256.

Notch signaling in ocular vasculature development and diseases

Guo-Rui Dou  1 , Lin Wang, Yu-Sheng Wang, Hua Han
Affiliations
Review

Notch signaling in ocular vasculature development and diseases

Guo-Rui Dou et al. Mol Med. .

Abstract

Ocular angiogenesis, characterized by the formation of new blood vessels in the avascular area in eyes, is a highly coordinated process involved in retinal vasculature formation and several ocular diseases such as age-related macular degeneration, proliferative diabetic retinopathy and retinopathy of prematurity. This process is orchestrated by complicated cellular interactions and vascular growth factors, during which endothelial cells acquire heterogeneous phenotypes and distinct cellular destinations. To date, while the vascular endothelial growth factor has been identified as the most critical angiogenic agent with a remarkable therapeutic value, the Notch signaling pathway appears to be a similarly important regulator in several angiogenic steps. Recent progress has highlighted the involvement, mechanisms and therapeutic potential of Notch signaling in retinal vasculature development and pathological angiogenesis-related eye disorders, which may cause irreversible blindness.

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Figures

Figure 1
Figure 1
Canonical Notch signaling and crosstalk with VEGF signaling. VEGF signaling up-regulates the expression of Notch ligands and receptors on ECs. Notch ligands on the signal-sending cell trigger Notch receptors on the adjacent signal-receiving cell, leading to receptor cleavage by ADAM and γ-secretase and the release of NICD. NICD translocates into the nucleus, where it associates with RBP-J, and converts RBP-J from a transcriptional repressor into an activator by recruiting transcriptional coactivators (CoA) to replace coreppressors (CoR). The transcription of target genes such as Hes are turned on. The p21 expression is also regulated by Notch activation. Notch signaling downregulates VEGFR2 and upregulates VEGFR1, leading to differentiation of tip and stalk cells, among other changes of ECs during angiogenesis.
Figure 2
Figure 2
Diverse roles of Notch signaling in regulating angiogenic ocular angiogenesis. Ocular vasculature formation is a finely ordered vascular system that relies on physiological angiogenesis. Pathological angiogenesis, on the other hand, results in a various angiogenesis related ocular diseases such as retinal neovascularization (RNV) and CNV. Notch signaling participates in vasculature formation and angiogenic ocular diseases by regulating vascular quiescence through p21 and Wnt signaling (1), angiogenic sprouting through tip formation and guidance (2), vessels maturation through EC-pericyte communication (3), EPC mobilization and function (4) and EC functions (5). Therefore, intervention of Notch signaling in each step of angiogenesis might have therapeutic potentials.
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